Is FLNC p.Pro1920Leu (c.5759C>T) pathogenic?

FLNC p.Pro1920Leu (c.5759C>T) is classified Conflicting classifications of pathogenicity in FLNC (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-06-29). AlphaMissense: likely pathogenic (0.9507); Very rare (popmax 0.00446%, eas); Associated with myofibrillar myopathy 5.

What condition is associated with FLNC p.Pro1920Leu (c.5759C>T)?

FLNC p.Pro1920Leu (c.5759C>T) is associated with myofibrillar myopathy 5, distal myopathy with posterior leg and anterior hand involvement, hypertrophic cardiomyopathy 26 (ClinVar).

How common is FLNC p.Pro1920Leu (c.5759C>T) in the general population?

FLNC p.Pro1920Leu (c.5759C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

How is Muscle filaminopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about FLNC p.Pro1920Leu (c.5759C>T)?

AlphaMissense predicts likely pathogenic (score 0.9507) — an in-silico prediction, not a clinical call.

FLNC p.Pro1920Leu

c.5759C>T · rs199714090 · VCV450485

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9507 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

myofibrillar myopathy 5

Computational evidence

Protein change
AlphaMissense	0.9507	likely pathogenic
REVEL	0.907	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.47 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 5,636 bp · p 8.4e-23 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,874 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000372% 6/1,613,972 alleles · very rare exomes 5/1,461,660 · genomes 1/152,312 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,437
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
South Asian	0.0011%	91,086
European (non-Finnish)	0.000169%	590,019

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: FLNC
Protein: p.Pro1920Leu
Coding: c.5759C>T
MANE Select: NM_001458
dbSNP: rs199714090
Type: single nucleotide variant
Location: chr7:128851545 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)

Full FLNC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

myofibrillar myopathy 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: distal myopathy with posterior leg and anterior hand involvement hypertrophic cardiomyopathy 26

For Muscle filaminopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

FLNC p.Pro1920Thr Uncertain significance ★★ ⚠ same residue
FLNC p.Pro1920= Likely benign ★ same residue
FLNC c.1047+1G>T Likely pathogenic ★★ same condition
FLNC c.1048-1G>A Likely pathogenic ★★ same condition
FLNC c.1210+1G>A Likely pathogenic ★★ same condition
FLNC c.1549+2T>G Likely pathogenic ★★ same condition
FLNC c.2007+1G>A Likely pathogenic ★★ same condition
FLNC c.2550+1G>C Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/flnc-p-pro1920leu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown